{"doi":"10.1101/2025.10.29.685293","title":"Transcriptional condensates at super-enhancers mediate pH-dependent transcriptional control in innate immunity","abstract":"Abstract Tissue acidification is a common feature of hypoxia, inflammation and solid tumor. Acidic pH regulates innate immune response in macrophages by weakening BRD4-containing transcriptional condensates. Yet how disruption of transcriptional condensates leads to gene-specific regulation of immune programs remain unclear. Here, we integrated ATAC-seq, ChIP-seq, and RNA-seq of primary murine macrophages and performed integrative epigenomics analyses to identify transcriptional regulators (TRs) with pH-sensitive regulatory potential and association to BRD4-dependent transcriptional condensates. We determined pH-dependent super-enhancers (SEs) by extended profiles of BRD4 binding and h3K27ac marks. We found RELA, IRF family, and STAT family as candidate TRs enriched at BRD4-associated, pH-sensitive SE regions. RELA and IRF3 preferentially occupied BRD4-associated and pH-sensitive SEs, and displayed markedly reduced binding under acidic conditions, aligning with BRD4 occupancy change. Correspondingly, immune-response genes within BRD4-associated, pH-sensitive SE regions, including Ch25h , Acp2 , Gda , and Ifit family, were significantly higher expressed at pH 7.4 than at pH 6.5. Together, these results reveal a set of TRs involved in BRD4-associated, pH-sensitive transcriptional condensates that coordinate macrophage gene activation under physiological conditions, providing mechanistic insight into how acidic stress modulates transcriptional condensates and immune responses.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":579566,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":253208,"name":"Zhongyang Wu","orcid":null,"position":1,"is_corresponding":false},{"id":244817,"name":"Zhe Zhong","orcid":"0000-0001-6114-3118","position":2,"is_corresponding":false},{"id":1490133,"name":"Xu Zhou","orcid":"0009-0000-4652-0907","position":3,"is_corresponding":false},{"id":43221,"name":"Chongzhi Zang","orcid":"0000-0003-4812-3627","position":4,"is_corresponding":false},{"id":1176227,"name":"Shengyuan Wang","orcid":"0000-0002-9264-4860","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:58:34.718602Z","pmid":"41279638","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}